Neuropeptides in Cancer: Friend and Foe?

Abstract

highly dynamic network of various cell types (e.g., cancer cells, endothelial cells, immune cells, fibroblasts) that exert differential effects on neuronal activity within the local environment. Thus, complex signaling between cancer and stromal cells in the TME results in altered firing rates of local nerves. Reciprocally, increased neuronal activity and subsequent release of classical neurotransmitters and/or neuropeptides within the TME results in enhanced cancer progression and subsequent metastasis in various preclinical models and clinical studies. [5][6][7][8][9] Nerves interact with multiple stromal cells in the TME where they indirectly promote tumor growth, progression, and subsequent metastasis. [10] Several studies have demonstrated that sympathetic nerve innervation and subsequent release of the neurotransmitter norepinephrine (NE) is increased in breast tumors. [6,8,9] However, recent work has demonstrated that there is an inverse relationship between tumor weight and norepinephrine content (i.e., larger the size of the tumor, the lower the levels of NE), despite increased innervation of sympathetic nerves within the TME. [11] These findings may be attributed to a relatively unexplored phenomenon: neuropeptide release within the TME. Neuropeptides are molecular messengers that regulate a variety of functions in the central and peripheral nervous systems via binding G-protein-coupled receptors (GPCRs) on target cells. One of the many functions of neuropeptides is serving as growth factors for normal cells via the activation of the heterotrimeric G protein Gq and subsequent synthesis of second messengers and engagement of tyrosine phosphorylation cascades. Neuropeptides act as neuromodulators, in that they can alter the response of neurons to neurotransmitters and other circulating signals, such as leptin, ghrelin, glucose, and insulin-all of which are affected during cancer progression. [12][13][14][15][16][17] For example, both neuropeptide Y (NPY) and hypocretin/orexin neurons appear to mediate some of the orexigenic effects of centrally administered ghrelin as administration of NPY receptor antagonists attenuated ghrelininduced feeding. Similarly, ghrelin-induced feeding was suppressed in orexin knockout mice, indicating that ghrelin may stimulate feeding through both the orexin and NPY systems. [18] However, neuropeptide signaling is exploited within cancer cells and many studies demonstrate the contribution of neuropeptides in tumor cell proliferation and migration, [19] with many major neuropeptides also potentially contributing to cancer processes (see Table 1). Additionally, neuropeptides exert direct Neuropeptides are small regulatory molecules found throughout the body, most notably in the nervous, cardiovascular, and gastrointestinal systems. They serve as neurotransmitters or hormones in the regulation of diverse physiological processes. Cancer cells escape normal growth control mechanisms by altering their expression of growth factors, receptors, or intracellular signals, and neuropeptid...

Involvement of neuronal factors in tumor angiogenesis and the shaping of the cancer microenvironment

“…Although by themselves, these factors may not be critical for cancer cell survival, they were shown to facilitate tumor growth in the context of chemotherapy. Given that neurotransmitters and neuropeptides can activate signaling pathways pertaining to cell proliferation and survival, such as the PI3K, MAPK and Akt pathways, their inhibition should constitute a relevant chemo- or targeted therapy sensitization strategy ( 132 ). Table 1 lists some of the reported effect of factors released by nerves within tumors and their reported effects on tumorigenesis.…”

Antitumor Strategies Targeting Peptidergic Systems

“…Several key findings have confirmed the role of peptides in cancer progression. These include the following: (1) peptides promote the growth of various cancer cells, which can contribute to tumor progression; (2) the same peptides can prevent programmed cell death in different types of cancer cells; (3) peptides facilitate the movement of cancer cells, which can lead to metastasis; (4) peptides encourage the growth of endothelial cells, which can contribute to angiogenesis and tumor development; (5) cancer cells produce and release peptides that promote the actions outlined above; (6) the same peptides released by cancer cells can also be produced and released by different cells within the tumor microenvironment, such as immune cells or nerve terminals; (7) the levels of peptides in the blood are elevated in patients with cancer compared to those in healthy individuals; and (8) the overexpression of peptidergic systems has been linked to cancer development, tumor size, and poor prognoses [15][16][17][18][19][20]. The microenvironment of a tumor is of utmost importance in the development of cancer as it is near immune cells, and the peptidergic systems regulate the response of these cells.…”

“…can contribute to angiogenesis and tumor development; (5) cancer cells produce and release peptides that promote the actions outlined above; (6) the same peptides released by cancer cells can also be produced and released by different cells within the tumor microenvironment, such as immune cells or nerve terminals; (7) the levels of peptides in the blood are elevated in patients with cancer compared to those in healthy individuals; and (8) the overexpression of peptidergic systems has been linked to cancer development, tumor size, and poor prognoses [15][16][17][18][19][20]. The microenvironment of a tumor is of utmost importance in the development of cancer as it is near immune cells, and the peptidergic systems regulate the response of these cells.…”

“…This is because peptides generally show poor bioavailability and a short half-life. However, it is essential to emphasize that some strategies are being developed to increase the therapeutic effects of peptides as well as their stability and delivery (e.g., peptide-loaded nanoparticles, peptide cyclization, conjugation of peptide drugs to natural/synthetic polymers, manipulation of the amino acid sequence, cell-targeting peptides, and cell-penetrating peptides) [5,6]. Some cell-penetrating short peptides show an antitumor action, and, in addition, they can also be used to carry anticancer cargo into tumor cells [7].…”

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

“…These peptides promote the mitogenesis/migration of tumor cells, exert an antiapoptotic action, and stimulate the growth of blood vessels and lymphangiogenesis. However, some peptides such as neuropeptide Y, orexin, and vasoactive intestinal peptide also exert an anticancer effect [ 7 ]. Furthermore, tumor cells release peptides acting through autocrine, paracrine, and endocrine (tumor mass) mechanisms [ 1 , 2 , 3 , 5 , 6 , 8 , 9 , 10 , 11 ].…”